Many human enzymes serve as targets for the action of pharmaceutically active compounds. Several classes of human enzymes that serve as such targets include helicase, steroid esterase and sulfatase, convertase, synthase, dehydrogenase, monoxygenase, transferase, kinase, glutanase, decarboxylase, isomerase and reductase. It is therefore important in developing new pharmaceutical compounds to identify target enzyme proteins that can be put into high-throughput screening formats. The present invention advances the state of the art by providing novel human drug target enzymes related to the sulfatase subfamily.
Sulfatases
The novel human protein, and encoding gene, provided by the present invention is related to the sulfatase family of enzymes, including estrone sulfatases. Specifically, the novel human protein of the present invention is a novel alternative splice form of a gene provided in Genbank gi5689491 and published PCT patent application WO200055629 (see the BLAST and Genewise alignments of the sequences of the present invention and the sequences of gi5689491 and WO200055629 provided in FIG. 2). The evidence supporting alternative splicing includes a different polyA signal used to create the protein of the present invention compared with the art-known protein; the stop codon at cDNA positions 1223–1225 and polyA signal at cDNA positions 1750–1756 are present in the genomic sequence; and the last exon of the cDNA of the present invention crosses the splicing site of the corresponding exon 5 of the art-known protein (these differences are illustrated in FIG. 2 in the BLAST and Genewise alignments of the sequences of the present invention and the sequences of gi5689491 and WO200055629).
Novel human sulfatases, such as the protein provided by present invention, are particularly useful as targets for treating cancer, particularly breast cancer. Sulfatases are important for generating estrone and 5-androstenediol from sulfated precursors. As stated by Purohit et al., (Mol. Cell Endocrinol Jan. 22, 2001; 171(1–2):129–135), “The development of inhibitors to block the formation of estrone and 5-androstenediol from sulfated precursors is an important new strategy for the treatment of breast cancer”. Thus, sulfatase inhibitors are useful for treating cancer and, consequently, novel sulfatase proteins are valuable as novel targets for the development of anti-cancer therapeutic agents. Purohit et al. found that non-steroidal and steroidal sulfamates, particularly a tricyclic coumarin sulfamate (“667 COUMATE”) and 2-methoxyestrone-3-O-sulfamate (2-MeOEMATE), inhibited estrone sulfatase activity and “offer considerable potential for development for cancer therapy”. The importance of sulfatases relating in breast cancer is further described in published PCT patent application WO200055629, “Novel Methods of Diagnosing and Treating Breast Cancer, Compositions, and Methods of Screening for Breast Cancer Modulators”.
Enzyme proteins, particularly members of the sulfatase enzyme subfamily, are a major target for drug action and development. Accordingly, it is valuable to the field of pharmaceutical development to identify and characterize previously unknown members of this subfamily of enzyme proteins. The present invention advances the state of the art by providing previously unidentified human enzyme proteins, and the polynucleotides encoding them, that have homology to members of the sulfatase enzyme subfamily. These novel compositions are useful in the diagnosis, prevention and treatment of biological processes associated with human diseases.